Significance Only ∼5% of individuals infected with Mycobacterium tuberculosis develop clinical TB in their lifetime. We previously reported that homozygosity for the P1104A variant of the TYK2 gene, found in ∼1/600 Europeans and ∼1/5,000 individuals from elsewhere (except East Asians and sub-Saharan Africans), was a monogenic etiology of TB in a genetically heterogeneous cohort of patients from non-European countries endemic for TB. Making use of the UK Biobank cohort, we report a strong enrichment of P1104A homozygotes in a British sample of 620 patients with TB (1%), relative to 114,473 controls (0.2%), 97% of whom were of European descent. Our findings suggest that homozygosity for the P1104A TYK2 variant may underlie TB in ∼1% of European patients.